Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41]O)[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:40]=[C:39]([CH2:41][I:25])[CH:38]=[CH:37][C:36]=1[N:43]1[S:47](=[O:49])(=[O:48])[N:46]([CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](=[O:56])[CH2:44]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CO)cc2OCc2ccccc2)S1(=O)=O
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CI)cc2OCc2ccccc2)S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. slurry of resin-bound PPh3 (850 mg, 2.5 mmol) in CH2Cl2 (10 mL) in a pressure vessel is added imidazole (200 mg, 2.8 mmol) and iodine (650 mg, 2.5 mmol). The mixture is vigorously stirred at 0° C. for 30 min. To the mixture is added a solution of 5-(2-benzyloxy-4-hydroxymethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (550 mg, 1.2 mmol) in CH2Cl2 (10 mL) dropwise. The vessel is sealed and heated to 45° C., with stirring, for 2 h. The reaction is allowed to cool to RT and the mixture is filtered through a plug of cotton to remove the resin. The organic solution is washed with sat. Na2SO3 and brine, then dried over MgSO4. The solvent is removed under reduced pressure to afford the title compound as a white solid which is used in the next step without further purification: (M+H)+=576.
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:16]([O:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:1]=1
Reactant: CCN(CC)CC
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: c1ccc(COCc2ccccc2)cc1
Reaction time: 72 h
Yield: 56.9 %

Procedure:
The sultam 3 (R2, R3=H; R10=t-Bu; n=2) (198 mg) was dissolved in methylene chloride along with copper (II) acetate (153 mg), triethylamine (426 mg), 4 Å molecular sieves (180 mg), and 4-benzyloxybenzeneboronic acid (384 mg). The reaction was stirred open to air for 3 days. The mixture was filtered and concentrated. Purification of the crude material by silica gel chromatography (10-45% ethyl acetate/hexanes) provided the sulfonamide 4 (R2, R3=H; R=4-benzyloxyphenyl; R10=t-Bu; n=2) (190 mg, 54%). MS found: (M+Na+MeCN)+=481. (39b) The sulfonamide 4 (R2, R3=H; R=4-benzyloxyphenyl; R10=t-Bu; n=2) (190 mg) was dissolved in methanol prior to the addition of 20% Pd(OH)2/C (20 mg). A hydrogen balloon was added, and the solution was stirred overnight. The hydrogen balloon was removed, and the solution was filtered and concentrated. This gave the phenol 4 (R2, R3=H; R=4-hydroxyphenyl; R10=t-Bu; n=2) (quant.) ready for subsequent reactions. MS found: (M+Na+MeCN)+=391. (39c) A solution of phenol 4 (R2, R3=H; R=4-hydroxyphenyl; R10=t-Bu; n=2) (149 mg), potassium carbonate (314 mg), and 2-methyl-4-chloromethylquinoline (87 mg) in acetonitrile was heated at reflux for 2 hr. The solution was cooled to rt, filtered, and concentrated. The crude material was purified by silica gel chromatography (20-65% acetonitrile/water) to provide ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=t-Bu; n=2) (140 mg) MS found: (M+H)+=483. (39d) To a solution of ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=t-Bu; n=2) (140 mg) in methanol was added thionyl chloride (3.0 g). The mixture was allowed to stir for 1 h and concentrated to give methyl ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=Me; n=2) (quant.). MS found: (M+H)+=441. (39e) The ester 4 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; R10=Me; n=2) (128 mg) was treated as in (35b) to yield the title hydroxamate 5 (R2, R3=H; R=4-[(2-methyl-4-quinolinyl)methoxy]phenyl; n=2) (15 mg). MS found: (M+H)+=442.
Reaction SMILES: [I-].[Na+].[CH:3]([NH:5][C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:7][C:8](=C)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].O>C(COC)OC.[Zn]>[CH:3]([NH:5][C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4]
Reactant: C=C(CCC(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CCC=CC(NC=O)(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 69.5 %

Procedure:
4.2 g of sodium iodide and 3.7 g of zinc were added to a solution of 2.4 g of the product A of Step C of Example 1 and the reaction medium in dimethoxyethane was refluxed in the presence of water with stirring for 2 hours. 50 ml of water were added and after filtration, extraction was carried out with methylene chloride. The extracts were dried and evaporated to dryness under reduced pressure to obtain 2.3 g of crude product which was chromatographed on silica. Elution with a cyclohexane ethyl acetate mixture (5-5) yielded 1.6 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:3]2[NH:4][CH:5]=[N:6][C:2]2=[N:1][C:17]=1[C:16]1[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:15]=1[O:14][CH3:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1cccc(C=O)c1OC
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc[nH]n1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1cccc(-c2nc3nc[nH]n3c2NC(C)(C)C)c1OC

Procedure:
Compound 36 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,3-dimethoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]O.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][O:17][C:14]([C:12]1[CH:11]=[CH:10][C:9]([NH:18][C:19]([C:21]2[NH:25][C:24]([C:26]#[N:27])=[CH:23][N:22]=2)=[O:20])=[C:8]([C:5]2[CH2:6][CH2:7][C:2]([CH3:28])([CH3:1])[CH2:3][CH:4]=2)[CH:13]=1)([CH3:15])[CH3:16]
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CN(C)CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOC(C)(C)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 60 °C
Yield: 11.1 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (60 mg, 0.16 mmol)(as prepared in Example 14, step (d)) in 1 mL of DCM was added 2-dimethylamino-ethanol (0.32 mL, 3.20 mmol), TFA (0.37 mL, 4.80 mmol), and the mixture heated to 60° C. for 6 h. The mixture was concentrated and the title compound purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-55% CH3CN in 0.1% TFA/H2O over 9 min to give 10 mg (11%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.26 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 5.77 (m, 1H), 3.52 (m, 2H), 3.30 (m, 2H), 2.91 (s, 6H), 2.34 (m, 2H), 2.11 (m, 2H), 1.64 (s, 6H), 1.60 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5O2, 450.3 (M+H). found 450.0.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[NH:3][N:2]=1)=[O:19])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCCC(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(CCCC(C)C)[nH]n1
Yield: 73.1 %

Procedure:
Hydrazine hydrate (0.943 mL, 1.91 mmol) was added to a stirring room temperature solution of 16 (0.4354 g, 1.91 mmol) in EtOH (1.9 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by TLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 96:4 Hexanes:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.3132 g (63.1%) of 17. 1H (CDCl3, 400 MHz): δ 9.60 (1H, broad s), 6.58 (1H, s), 4.34 (2H, q, J=7.2 Hz), 2.66 (2H, t, J=7.7 Hz), 1.67-1.57 (2H, m), 1.58 (1H, m), 1.36 (3H, t, J=7.2 Hz), 1.24-1.15 (2H, m), 0.85 (6H, d, J=6.5 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 162.22, 106.59, 61.17, 38.58, 27.99, 27.20, 26.57, 22.72, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 22.72, 14.48; CH2 carbons: 61.17, 38.58, 27.20, 26.57; CH carbons: 106.59, 27.99 ppm. HPLC: 10.072 min.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=O.COC(OC)(C)C>>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][C:11]([CH3:13])([CH3:10])[O:5][CH2:4]1
Reactant: CC(C)=O
Reactant: OCC(CO)(CBr)CBr
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CBr)(CBr)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TsOH monohydrate (0.1 eq) was added at 0° C. to a 0.2M solution of 2,2-bis(bromomethyl)propane-1,3-diol in acetone/2,2-dimethoxypropane (10:1) and the solution was stirred for 2 h at RT. Filtration over a pad of neutral alumina with EtOAc afforded the title compound as a white solid after evaporation of the solvent in vacuo (quant). 1H NMR (300 MHz, CDCl3, 300 K) 3.80 (s, 4H), 3.58 (s, 4H), 1.42 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[O:14]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][O:14][NH:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)C=O
Reactant: COc1cccc(C(N)=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)CONC(=O)c1cccc(OC)c1

Procedure:
3-Methoxybenzamide (13.25 g) and methyl glyoxylate (7.72 g) in toluene (150 ml) were heated under reflux in a Dean-Stark apparatus for 6 hours. On cooling the mixture the product separated and was crystallised from toluene. Yield, 12.0 g, m.p. 93°-94°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12](C(OCC)=O)([C:16]([O:18]CC)=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>C(O)(C)(C)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To the diethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7,7-dicarboxylate (10.5 g, 29.5 mmol) was added water (25 mL) and concentrated (12 N) hydrochloric acid (75 mL). The mixture was heated at reflux for 8 h. The volatiles were evaporated, and the residue was dissolved in water (10 mL) and the pH of the solution was adjusted to pH 8 with 10% aqueous sodium bicarbonate. Di-tert-butyl dicarbonate (8.5 g, 39 mmol) in tert-butanol (60 mL) was added and the reaction was stirred overnight at ambient temperature. Ethyl acetate (100 mL) was added to the reaction and the pH of the solution was adjusted to pH 3 with 2 M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×200 mL) and brine (100 mL), dried (anhydrous sodium sulfate), concentrated (rotary evaporation), and purified by silica gel column chromatography to give 5.1 g of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, as a white solid (1H NMR (CDCl3, 300 MHz): δ 3.59-3.40 (m, 2H), 3.36-3.05 (m, 2H), 3.02-2.76 (m, 2H), 2.65-2.60 (m, 1H), 2.24-2.04 (m, 2H), 1.85-1.66 (m, 2H), 1.46 (s, 9H); MS (m/z): 256 (M+1), 200 (M+1-56)).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[C:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)(=O)C>[C:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:15]1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Reactant: CC(=O)C(=O)O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1cc(-c2cc(C(=O)O)c3ccccc3n2)c2ccccc21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 3 %

Procedure:
To a 500 mL round bottom flask was added 27.2 g (0.31 mol) of pyruvic acid (Lancaster), N-Boc-indole-3-carboxaldehyde (0.16 mol) and 200 mL of acetic acid. The reaction mixture was heated at 85° C. until all the solid material had dissolved (˜30 min). Then aniline (0.31 mol) was added and the reaction mixture was stirred for 90 minutes at 85° C. The precipitate was filtered hot in a fritted funnel and washed with acetic acid (2×50 mL) and then with ether (2×50 mL). The solid filter cake was dried in vacuo to yield 2-(N-Boc-3-indolyl)-4-quinolinecarboxylic Acid (3-50% yield) of pure (>95%) material.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29](F)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]5[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[C:29]([NH:37][CH2:38][C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)[CH:28]=5)[CH2:22][CH2:21]4)[C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccnc1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(F)c5)CC4)cccc3[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5ccc([N+](=O)[O-])c(NCc6cccnc6)c5)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a mixture of 2-(4-tert-Butyl-phenyl)-4-[4-(3-fluoro-4-nitro-benzyl)-piperazin-1-yl]-1H-benzoimidazole (75 mg, 0.15 mMol) in dimethylformamide (2 mL) under nitrogen was added 3-(Aminomethyl) pyridine (0.078 mL, 0.77 mMol) and the resulting solution stirred overnight at room temperature. Upon arrival the reaction mixture was diluted with ethyl acetate (50 mL) and washed three times with water (50 mL) followed by brine (50 mL). The organics were dried with magnesium sulfate, filtered, and evaporated to dryness. Purification by flash column chromatography on silica gel and 5% methanol in dichloromethane as eluant yielded 50 mg of (5-{4-[2-(4-tert-Butyl-phenyl)-1H-benzoimidazol -4-yl]-piperazin-1-ylmethyl}-2-nitro-phenyl)-pyridin-3-ylmethyl-amine as a yellow-orange solid (56% yield). 1H NMR (CDCl3): δ=9.24 (s, 1H), 8.66 (s, 1H), 8.55 (m, 1H), 8.43 (m, 1H), 8.16 (d, 1H, J=7.5 Hz), 8.03 (m, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.69 (d, 1H, J=6.0 Hz), 7.49 (d, 2H, J=7.5 Hz), 7.14 (m, 1H), 7.04 (d, 1H, J=6.0 Hz), 6.87 (s, 1H), 6.73 (m, 1H), 6.59 (d, 1H, J=6.0 Hz), 4.60 (m, 2H), 3.55 (m, 6H), 2.68 (m, 4H), 1.34 (s, 9H). LC/MS (Method A), rt=1.05 mins., purity=98.5%, calculated mass=575, [M+H]+=576, [M−H]−=574.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14](O)[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:53])(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14]([Cl:53])[C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:11]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([C:33]([F:38])([F:37])[CH2:34][CH2:35][CH3:36])[N:29]=[CH:28][C:27]=3[C:26]([CH3:40])([CH3:39])[CH2:25]2)=[O:23])[CH2:10][C@H:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(O)c1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(F)(F)c1cc2c(cn1)C(C)(C)CN2C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1C(Cl)c1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To (2R,5R)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-(hydroxy-thiazol-2-yl-methyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.076 g, 0.13 mmol) and triethylamine (36 μL, 0.3 mmol) in DCM (0.6 mL) cooled with an ice bath under nitrogen was added methanesulfonyl chloride (12 μL, 0.2 mmol). The reaction was stirred at this temperature for 1 h and then warmed room temperature for 18 h. Saturated aqueous sodium bicarbonate was added and the mixture extracted with EtOAc. The combined organics were washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.03 g). MS: [M+H]+=612.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([C:38](OCC)=[O:39])[NH:29]1>CCO>[O:27]=[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([C:38]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:16])=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=2)=[O:39])[NH:29]1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CN)c2)cc1)C(C)C
Reactant: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Solvent: CCO
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Yield: 86 %

Procedure:
A suspension of methyl N-{[3′-(aminomethyl)biphenyl-4-yl]sulfonyl}valinate obtained in Reference Example 94 (0.300 g, 0.797 mmol) and ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate obtained according to the methods described in Journal of Organic Chemistry (1978), 43(23), 4485-7 and the like (0.145 g, 0.664 mmol) in EtOH (9 mL) was stirred at 90° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.375 g, 86%).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][C:12](=[O:39])[CH2:13][CH2:14][C:15]([CH3:38])=[CH:16][CH2:17][C:18]1[C:19]([O:31]CC[Si](C)(C)C)=[C:20]2[C:24](=[C:25]([CH3:29])[C:26]=1[O:27][CH3:28])[CH2:23][O:22][C:21]2=[O:30])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.N1C(C)=CC=CC=1C>C(#N)C>[OH:31][C:19]1[C:18]([CH2:17][CH:16]=[C:15]([CH3:38])[CH2:14][CH2:13][C:12]([NH:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[O:39])=[C:26]([O:27][CH3:28])[C:25]([CH3:29])=[C:24]2[C:20]=1[C:21](=[O:30])[O:22][CH2:23]2
Reactant: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CCC(=O)NCCP(=O)(O)O)C(=O)OC2
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a solution of (2-{6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoylamino}-ethyl)-phosphonic acid diethyl ester (36.6 mg, 0.063 mmol) in acetonitrile (1 mL) was added TMSBr (81 μL, 0.63 mmol) followed by 2,6-lutidine (73 μL, 0.63 mmol). The reaction was allowed to proceed overnight, when it was completed as judged by LCMS. The reaction mixture was quenched with MeOH and concentrated to dryness. The residue was purified by preparative reverse-phase HPLC to afford 5.8 mg (29%) of desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.80 (s, 3H), 2.14 (m, 5H), 2.25 (m, 4H), 3.35 (m, 2H), 3.38-3.38 (m, 2H), 3.75 (s, 3H), 5.23 (s, 3H) ppm; 31P (121.4 MHz, CD3OD) δ 26.03 ppm; MS (m/z) 426 [M−H]−, 428 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1C(C)=NC(C)=NC=1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1ncc(Cl)c(C)n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1Cl
Temperature: 25 °C

Procedure:
2,4,5-trichloropyrimidine (1.83 g, 10 mmol) was dissolved in THF:NMP (10:1, 100 mL) at room temperature and iron(III) acetylacetonate (0.71 g, 2.0 mmol) was added under N2. MgBrMe (3M, 12 mmol) was added drop-wise via syringe. The mixture was cooled to RT, progress was verified by LC-MS: typical results show product vs starting material vs 5-chloro-2,4-dimethylpyrimidine side product ˜2:2:1 ratio. The reaction was quenched with ice cold, saturated ammonium chloride (, 100 mL), extracted with ethyl acetate (100 mL), washed with brine (100 mL, ×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by silica gel chromatography (5% ethylacetate/hexane) to yield the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(OC(=O)C)C.C(O)C>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 mmol) in ethylacetate (100 mL) and ethanol (100 mL) and add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M in hexane) at room temperature and stir the solution for 1 h 30 min. Remove the solvent under reduced pressure to afford the title compound (3.30 g, quantitative). 1H NMR (CDCl3, 300 MHz) δ 2.43 (s, 3H), 3.89 (s, 3H), 5.11 (brs, 2H), 6.52 (m, 2H), 7.08 (t, J=7.7 Hz, 1H). MS (ES+): 166 (M+H).